Cigarette smoking continues to be a leading cause of cancer in the United States. Although smoking rates have declined in the general population, there are subgroups of smokers for whom smoking is disproportionately high. Patients with major psychiatric disorders, such as those with depression or schizophrenia, smoke at higher rates than normal controls. This increased smoking rate contributes to their heightened risk of mortality due to smoking-related illnesses, including cancer, cardiovascular disease and stroke. The aim of this project is to study the role of serotonin in regulating cigarette cravings among normal controls and patients with major psychiatric disorders. Using the tryptophan- depleting challenge test, a method known to acutely and transiently deplete plasma and brain tryptophan levels, and presumptively brain serotonin, we aim to test whether cigarette cravings are differentially altered in three groups of smokers. The groups to be studied present different types of serotoninergic dysregulation: smokers with major depression (a psychopathology associated with a functional deficiency in serotonin), smokers with schizophrenia (psychopathology associated in part, to excess serotonin responsivity) and normal controls (presenting no dysfunction in serotonin). Current theories of substance abuse posit two key constructs associated with drug cravings. One is appetitive or compulsive: the drug is craved because of subjective mood states. The other is appetitive or compulsive: the drug is craved because obsessional cognitions prime responses to drug-related cues and make drug self- administration a powerful incentive. The primary study hypothesis is that both the affective and appetitive cravings for cigarettes will changes after acutely depleting plasma tryptophan, but that the direction of change will be different across the groups. Results will enhance understanding of the neurochemical and behavioral process of cigarette craving and will have implications for designing behavioral and pharmacologic treatments for tobacco use.